Bibliometrics Analysis of Research Progress of Electrochemical Detection of Tetracycline Antibiotics

Tetracycline is a broad-spectrum class of antibiotics. The use of excessive doses of tetracycline antibiotics can result in their residues in food, posing varying degrees of risk to human health. Therefore, the establishment of a rapid and sensitive field detection method for tetracycline residues is of great practical importance to improve the safety of food-derived animal foods. Electrochemical analysis techniques are widely used in the field of pollutant detection because of the simple detection principle, easy operation of the instrument, and low cost of analysis. In this review, we summarize the electrochemical detection of tetracycline antibiotics by bibliometrics. Unlike the previously published reviews, this article reviews and analyzes the development of this topic. The contributions of different countries and different institutions were analyzed. Keyword analysis was used to explain the development of different research directions. The results of the analysis revealed that developments and innovations in materials science can enhance the performance of electrochemical detection of tetracycline antibiotics. Among them, gold nanoparticles and carbon nanotubes are the most used nanomaterials. Aptamer sensing strategies are the most favored methodologies in electrochemical detection of tetracycline antibiotics.


Introduction
Tetracycline antibiotics are a broad-spectrum class of antibacterial substances isolated from the actinomycete Streptomyces aureofaciens. Te tetracyclines have been used for a long time, but they are still widely used today [1]. Tetracycline is used in the livestock and poultry industry to treat diseases such as intestinal infections. Making meat from livestock and poultry before the end of the rest period can result in tetracycline residues. Residues of tetracycline are now being found in meat and dairy products, including milk, honey and eggs [2]. When we consume these products daily, the residual antibiotics enter our body through the food chain and may cause allergic reactions or make our body resistant to the drugs. Tetracycline antibiotics are widely used in various felds because of their broad antibacterial spectrum and low cost. Because of the antibacterial properties of the antibiotics themselves, the ecological environment is seriously afected by tetracycline antibiotics [3]. When tetracycline is used in humans or animals, the drug is excreted as a prodrug or metabolite with the metabolism, and most of it enters the soil and water bodies. Under the action of various environmental factors, it can produce transfer, transformation or enrichment in plants and animals [4]. Whether in its original form or metabolites, the drug remains active during the migration process and can cause severe efects on microorganisms, aquatic organisms and insects. Only a small percentage of tetracycline is left in the animal's body after use. Te toxicity of consuming this type of food does not manifest in a short period [5]. However, prolonged ingestion of food containing residual antibiotics can lead to various organ lesions due to accumulation efects. For example, tetracycline antibiotics can bind to calcium in the bones and have an inhibitory efect on the growth of human bones and teeth. Tetracycline taken orally by pregnant women in late pregnancy can also be deposited in the fetal dental tissues and afect the development of fetal milk teeth and permanent teeth. Terefore, long-term consumption of tetracycline can seriously afect human health [6].
So far, the detection methods of tetracycline include microbiological method, immunoassay, thin-layer chromatography, high-performance liquid chromatography (HPLC), liquid chromatography-mass spectrometry, spectroscopic analysis, and electrochemical method [7]. Different detection methods have diferent advantages and disadvantages, and their sensitivity and detection limits are also diferent. Among them, the microbiological method is currently recognized and widely used to determine the classical method of tetracycline antibiotic residues. Tis method is used to detect tetracycline antibiotics under mature conditions and with high accuracy. However, this assay is difcult to achieve the strong specifcity and high accuracy required for the assay due to the lack of anti-interference ability [8]. At the same time, the method is complicated and time-consuming for the pre-treatment of the sample. HPLC has the advantages of high efciency, rapidity, sensitivity and high detection rate, especially for the simultaneous detection of multiple substances. Terefore, HPLC is widely used in food hygiene departments to detect antibiotic residues in animal food [9].
In recent years, electrochemical analysis techniques have been used for the purpose of efcient long-term online monitoring of environmental pollutants [10][11][12][13][14][15]. Moreover, the simple principle of electrochemical detection, easy operation of the instrument and low cost of analysis and testing is widely used in pollutant detection. Tis method is characterized by high sensitivity, high accuracy and good selectivity, and the limit of detection of the measured substance can reach 10 −12 M. Electrochemical analysis techniques have a series of diferent methodologies, including polarimetric analysis, molecular imprinting techniques and chemically modifed sensors. For now, researchers are still searching for new, faster and more sensitive methods to detect tetracycline residues, such as immunosensors, enzyme sensors and aptamer sensors. So far, the electrochemical detection of tetracycline has been reviewed by several papers [16][17][18]. Tese reviews introduce the diferent methodologies and interpret the highlighted work. In this review, we attempt to analyze and review this topic statistically using a bibliometric approach. Bibliometric analysis is a literature and information mining method based on mathematical statistics. It can refect research trends and hotspots through clustering relationships of keywords in the literature and has become an important tool for global analysis in various scientifc felds [19][20][21][22][23][24]. Tis article hopes to analyze the collaborative networks and directions of investigation on this topic.

Data and Analysis Method
Two bibliometrics software have been used in this systematic literature review. Te frst is CiteSpace, developed by Dr. Chaomei Chen, a professor at the Drexel University School of Information Science and Technology [25][26][27][28]. CiteSpace 6.1R2 was used to calculate and analyze all documents. COOC is another emerging bibliometrics software [29]. COOC12.6 was used to analysis of country contribution and keywords co-occurrence. We used the core collection on Web of Science as a database to assure the integrity and academic quality of the studied material. "Tetracycline electrochemical sensor" or "tetracycline electrochemical detection" or "tetracycline electrochemical determination" has been used as a "Topic." Te retrieval period was indefnite, and the date of retrieval was June, 2022. 232 articles (including 5 early access) were retrieved (review and proceeding paper were not included in this survey).

Developments in the Research Field
3.1. Literature Development Trends. Te number of papers published is an important indicator used to measure whether a topic is widely attracting the attention of scholars. Figure 1 shows the annual and cumulative publications on electrochemical detection of tetracycline from 1995 to 2021. As can be seen, there were only sporadic reports on this topic before 2004. Te earliest paper was published in 1995. Novaknepekli et al. [30] reported the preparation of doxycycline antibiotic sensors using a potential sensing strategy. In 1996, Tanase et al. [31] investigated the electrochemical reduction of tetracycline at a mercury drop electrode using alternating current polarography. Tey found that the reduction waves of tetracycline are very complex and that the electrolyte's concentration and pH signifcantly afect the assay results. In 1998, Tanase et al. [32] not only investigated minocycline by alternating current polarography but further employed voltammetry. Zhou et al. [33] investigated tetracycline, chlortetracycline and oxytetracycline antibiotics using capillary zone electrophoresis-rapid cyclic voltammetry in 1999. Tis early series of work investigated the electrochemical properties of tetracycline antibiotics. Tese results laid the foundation for later highly sensitive sensing assays for tetracycline antibiotics. From 2004-2013, this topic entered a period of steady development. Tis topic has been published every year, with the number of papers ranging from 2-6. Tis topic had its frst growth between 2014-2017. Te annual number of papers published in this period was more than 10. Te second rapid growth in this topic started in 2018 and peaked at 32 papers in 2019. Te annual number of papers published in both 2020 and 2021 is 29. As of July 2022, there have been 27 publications on this topic this year, representing another stable publication phase for this topic without a signifcant downward trend. Tis topic is now at the most active stage in its entire development history. Figure 2 shows a tree diagram of the top 9 journals publishing the number of electrochemical detection of tetracycline antibiotics. As seen from the fgure, the journals that published the most papers on this topic all belonged to analytical chemistry, with Sensor and Actuators B-Chemical publishing the highest number of papers. Since this topic focuses on detecting tetracycline antibiotics using electrochemical techniques, the fgure includes, in addition to traditional analytical chemistry journals, those focusing on electroanalytical chemistry, including Electroanalysis, Journal of Electroanalytical Chemistry, and Biosensors & Bioelectronics. Notably, all journals in this fgure are classical journals in analytical chemistry and do not include journals launched in recent years. Tis represents that traditional analytical chemists favour the survey on this topic.

Journals, Cited Journals and Research Subjects.
In addition to the number of papers published by the journal on the topic, the frequency with which the journal cited papers related to the theme is also an important indicator. Table 1 shows the top 15 cited journals on the electrochemical detection of tetracycline antibiotics. Most of the journals in Figure 2 are included in Table 1, representing that they not only publish the most papers on this topic but are also most frequently cited in papers on this topic. Journals related to analytical chemistry, especially electroanalytical chemistry, continue to dominate Table 1. However, Table 1 also provides some additional information. Tis topic will also cover the Journal of Chromatography A, ranked eighth in Table 1, representing the chromatographic technique to detect tetracycline antibiotics. Based on our understanding of the feld of electrochemical sensors, chromatography-related analytical techniques for the separation and detection of tetracycline are often used as a comparison to corroborate the performance of the proposed electrochemical sensors. In addition, Food Chemistry and Food Control appear in Table 1 to represent that the main application area for tetracycline assays is food quality control.
To further explore the information that journals provide, we constructed a co-occurrence network of cited journals related to the electrochemical detection of tetracycline antibiotics ( Figure 3). In this fgure, we have not labelled most of the journals discussed in Figure 2 and Table 1. Te location at the centre of the fgure contains the journals mentioned above. However, this co-occurrence fgure provides some additional information.
(1) In addition to some classic analytical chemistry journals, the International Journal of Electrochemical Science and Sensor-Basel also have a high frequency of appearances on this topic.
(2) In the upper centre of the co-occurrence fgure are two journals with high centrality (purple circles).
Tere are Chemistry of Materials and Advanced Functional Materials, representing materials science is an important infuence on this topic's development.
(3) Te periphery of the co-occurrence fgure contains several journals focused on interface research, including Journal of Colloid and Interface Science, Applied Surface Science, and Langmuir. Signal changes in electrochemical sensors depend on the interface's chemical reactions. Terefore, it is important to investigate the nature of the interface for a sensor assembly.
(4) Te periphery of the co-occurrence fgure also includes a series of journals related to environmental science, such as Applied Catalysis B: Environmental, Journal of Hazardous Materials, Water Research, etc. Tis represents the application area of this topic, in addition to the food presented in Table 1 and the environmental feld.  Table 2 shows which journal was published for the frst time on this topic in 2021 and 2022. As can be seen, a series of materials science-related journals appear. A series of materials science-related journals are starting to publish papers on this topic. Tis confrms the above speculation that materials science innovations signifcantly impact the performance of electrochemical sensors. In addition, some bio-related journals also appear in Table 2, representing the possibility that electrochemical sensing technology has been applied to detect tetracycline antibiotics in biological samples.
Te category of the published paper can refect the evolution of the topic. Table 3 shows the evolution of the category of the electrochemical detection of tetracycline antibiotics over time. It can be seen that this topic in the early days involved mainly the felds of chemistry and biology. From 2009 onwards, categories related to materials science started to play an important role gradually. From 2012 onwards, categories of application areas related to tetracycline antibiotics are also included in the topic. Figure 4 shows the top 12 countries with the most publications on electrochemical detection of tetracycline antibiotics. China contributed the most signifcant number of papers, at 48.65%. Te fact that China has published nearly half of the papers on this topic can be attributed to three reasons. First, China has a large community of scientifc and technical personnel and therefore plays an important role in academic research. Second, electrochemical analysis is a feld with a long history in China. It has a very broad market in China for commercial products. Finally, tetracycline is widely used in China's farming industry, making the environmental pollution it causes a signifcant challenge. Iran and India also play an essential role in this topic, contributing 12.61% and 5.41% of the papers, respectively. Brazil, USA, France, Tailand and Romania contributed more than 4% of the papers. As seen from the fgure, this theme has attracted much attention in Asia, probably because Asian countries have been using many tetracycline antibiotics. At the same time, the topic has attracted several countries in South America and Europe due to the widespread use of tetracycline antibiotics worldwide.  Talanta (10) Electroanalysis (6) Microchimica Acta (12) Sensors and Actuators B-Chemical

Geographic Distribution.
Analytical Chemistry (7) Analytica Chimica Acta Analytical Methods (6) Biosensors & Bioelectronics (8) Journal of Electroanalytical Chemistry (6) Figure 2: Top 9 journals that published articles on the electrochemical detection of tetracycline antibiotics. Tis trend is directly correlated with the two increases in the number of papers published in Figure 1.
Although many countries are involved in this topic, it does not form a very complex network of cooperation. Figure 6 shows the institutional cooperation network for this topic. It can be seen that this topic has formed 2 main collaborative networks so far. Te frst collaborative network is led primarily by the Chinese Academy of Sciences and Table 2: List of journals has published paper for electrochemical detection of tetracycline antibiotics in the last two years.
Year Journals 2022 Applied nanoscience; diamond and related materials; environmental pollution; inorganic and nano-metal chemistry; journal of cleaner production; journal of materials science; journal of materials science-materials in electronics; journal of molecular liquids; journal of photochemistry and photobiology a-chemistry; journal of solid state chemistry; Korean journal of chemical engineering; spectrochimica acta part a-molecular and biomolecular spectroscopy 2021 Acs applied materials & interfaces; adsorption science & technology; biotechnology and applied biochemistry; chemosensors; international journal of environmental analytical chemistry; journal of fuorescence; journal of food measurement and characterization; journal of physical chemistry c; journal of sensors; nanomaterials; optical materials; polymer bulletin

Keyword Analysis and Evolution of the Field
Te most efective way to understand the direction of investigating concerns in a topic is the analysis of keywords. Table 3 lists the top 15 keywords in this topic. Since this topic is about the electrochemical detection of tetracycline, the most frequent keyword is related to antibiotics and electrochemistry. In addition, some other keywords provide information on the diferent research directions on this topic. For example, milk is ranked 5th in Table 4 with a total of 32 occurrences, representing that it is the most frequently used real sample for detecting tetracycline. Te quality of milk is extremely important, but the reality is that cows are susceptible to mammary gland disease, which can signifcantly decline some milk quality [34]. To avoid this quality risk, some dairy farmers inject their cows or add antibiotics to their feed to prevent them from contracting diseases [35]. Tetracycline is widely overused because of its good antibacterial efect and low price. Cows are usually treated with intramuscular or intravenous injections [36]. After circulation, the antibiotics end up in the udder, which can quickly end up in the milk. In other cases, injections are also given directly into the cow's lesion, a method that is more likely to produce antibiotic residues in the milk. If cow's milk or dairy products containing antibiotic residues reach the market, people unknowingly drink them to accumulate low doses of antibiotics [37]. Te benefcial bacteria in the human intestine will be afected by the ingested antibiotics, giving room for the growth of pathogenic bacteria and causing local or even systemic infections in the body. In addition, water also appears in Table 4, representing the importance of tetracycline detection in water bodies. Te primary sources of tetracycline antibiotics in the environment include industrial efuents, farming antibiotics, and medical antibiotics [38].
Nanoparticle and gold nanoparticle are ranked 6th and 12th respectively in Table 4, representing that nanomaterials signifcantly infuence this topic. In the last section of the journal analysis, we found a series of material science journals appearing on this topic, representing the synthesis and application of new materials that can improve the performance of electrochemical sensors [39]. Among them, metallic nanomaterials, especially noble metal nanomaterials, are most widely used in analytical assays. For example, nano gold and nano platinum have good biocompatibility and can maintain the activity of enzymes [40]. Carbon nanotubes also appear in Table 4, representing that it is also widely used as a material for electrochemical sensor preparation in this topic. Carbon nanotubes are seamless tube-like, quasi-one-dimensional carbon materials with nanoscale diameters formed from convoluted graphene sheets. Te carbon atoms in the tubes are mainly bonded by sp 2 hybridization to form hexagonal lattice-like graphene sheets. Carbon nanotubes can be classifed into single-walled carbon nanotubes (SWCNTs) and multi-walled carbon nanotubes (MWCNTs), depending on the number of carbon atom layers. Carbon nanotubes are widely used in electrochemistry because of their large specifc surface area and low resistivity and are considered excellent materials for nanodevices and interconnect devices [41].  Another important keyword in Table 4 is aptasensor. Te aptamer is a class of single-stranded oligonucleotides (DNA, RNA and modifed RNA) that can be synthesized by exponentially enriched ligand phylogenetic techniques (SELEX). It possesses the afnity to bind specifcally to the corresponding target molecule [42]. Te specifc binding of the aptamer to the corresponding target molecule is based on the diversity of single-stranded nucleic acid structures and their spatial conformations. Compared to common chemical antibodies, aptamers have an advantage in specifcity and selectivity. In addition, the aptamer is synthesized in vitro and a shorter cycle, unlike antibody preparation which takes at least fve or six months [43]. At the same time, the aptamer is chemically stable, such as a certain degree of thermal complexation, and easy to preserve. More importantly, various groups can be modifed on the aptamer as needed, such as functionalized groups like sulfhydryl, amino, and hydroxyl groups. Teir application with nanomaterials such as nanogold can be combined into Au-S bond, Au-NH 2 bond, etc., which facilitates the efective immobilization of aptamers [44]. Terefore, aptasensor is a detection method that combines highly sensitive sensor technology with aptamer and target detector specifc response, which has the advantages of both high selectivity of aptamer analysis and high sensitivity of the electrochemical analysis.
Cluster analysis can further understand the diferent directions of investigation in this topic. Figure 7 shows that 13 clusters were formed after clustering the keywords. On the whole, many clusters have overlapping areas between them, indicating that their contents have more similarities with each other. Table 5 describes the clusters and their ID, size (number of papers), silhouette, and respective keywords.

Conclusion and Perspectives
Nowadays, the main detection techniques for tetracycline antibiotics are HPLC, HPLC/MS, UV and fuorescence methods. Although the detection limits of these methods can meet the experimental requirements, the equipment costs are expensive, the sample analysis methods are complicated, and the real-time monitoring of pollutants cannot be achieved. Terefore, it is necessary to develop simple, inexpensive, fast and efcient electrochemical sensors with high accuracy. Tis review provides a bibliometrically based review of the development of electrochemical detection of tetracycline antibiotics from 1995-2022. Te statistical analysis led to the following conclusions: (1) Studies on electrochemical detection of tetracycline antibiotics have been reported since 1995 but did not receive much attention immediately. Papers on this topic started to receive gradual attention in 2004 and entered a period of rapid growth in 2014. (2) Te investigation of this topic has attracted many scholars from Asia and South America. Among them, China, Iran and India have contributed a large number of papers on this topic. However, this topic has not resulted in extensive international collaboration. (3) Papers on this topic are mainly published in classical analytical chemistry, especially in journals related to electrochemistry. Materials science-related journals have also started to publish papers on this topic in recent years. Developments and innovations in materials science can enhance the performance of electrochemical detection. Among them, gold nanoparticles and carbon nanotubes are the most used nanomaterials to enhance electrochemical sensing performance. (4) Although tetracyclines are electrochemically active and can be oxidized and reduced on common electrode surfaces. However, more sensitive and selective detection of tetracycline antibiotics can be achieved using aptamers. (5) Te main application scenarios for electrochemical detection of tetracycline are the detection of water and food (especially milk).
Meanwhile, based on the review of this topic, we believe that the following issues need to be investigated regarding the electrochemical detection of tetracycline: (1) Samples containing tetracycline often contain other substances, so the anti-interference of electrochemical detection techniques is a challenge that needs to be addressed. (2) How to improve the detection efciency of electrochemical sensors is also an important challenge. Conventional reusable electrodes can become contaminated during testing. Terefore, how to regenerate the electrode or improve the service life is also very important.
(3) Current electrochemical sensors still rely on sampling a sample. How to achieve instant detection is also a future challenge.

Data Availability
No data were used to support this study.

Conflicts of Interest
Te authors declare that they have no conficts of interest.

Authors' Contributions
Conceptualization, L. F. and H. K.; methodology, L. F. and X. L.; software, X. L. and D. W.; validation, D. W.; formal analysis, D. W. and X. L.; writing-original draft preparation, D. W. and X. L.; writing-review and editing, L. F. and D. W.; supervision, L. F. and H. K.; project administration, L. F. All authors have read and agreed to the published version of the manuscript.